Quinuclidine derivatives and medicinal composition thereof

Abstract

Quinuclidine derivatives represented by general following general formula (I), salts, N-oxides or quaternary ammonium salts thereof, and medicinal compositions containing the same. ##STR1## The compound has an antagonistic effect on muscarinic M 3 receptors and is useful as a preventive or remedy for urologic diseases, respiratory diseases or digestive diseases.

We claim: 
     
       1. A quinuclidine derivative represented by the following formula (I): ##STR344## where the symbols in the formula have the following meanings: Ring A: (1) an aryl group having 6 to 14 carbon atoms   (3) a cycloalkyl group having 3 to 8 carbon atoms   (4) a cycloalrenye group having 3to 8 carbon atoms; wherein groups (1) to (5) above may be unsubstituted or substituted by one or more substituents selected from the group consisting of a halogen atom, a hydroxyl group, a lower alkoxy group, a carboxyl group, a lower alkoxycarbonyl group, a lower acyl group, a mercapto group, a lower alkylthio group, a sulfonyl group, a lower alkylsulfonyl group, a sulfinyl group, a lower alkylsulfinyl group, a sulfonamido group, a lower alkanesulfonamido group, a carbamoyl group, a thiocarbamoyl group, a mono- or di-lower aklylcarbamoyl group, a nitro group, a cyano group, an amino group, a mono- or di-lower alkylamino group, a methylenedioxy group, an ethylenedioxy group, and a lower alkyl group which may be substituted by a halogen atom, a hydroxyl group, a lower alkoxyl group, an amino group or mono- or di-lower alkylamino group     X: a single bond or a methylene group;   R: a halogen atom, a hydroxyl group, a lower alkoxy group, a carboxyl group, a lower alkoxycarbonyl group, a lower acyl group, a mercapto group, a lower alkylthio group, a sulfonyl group, a lower akylsulfonyl group, a sulfinyl group, a lower alkylsufinyl group, a sulfonamido group, a lower alkanesulfonamido group, a carbamoyl group, a thiocarbamoyl group, a mono- or di-lower alkylcarbamoyl group, a nitro group, a cyano group, an amino group, a mono- or di-lower alkylamino group, a methylenedioxy group, an ethylenedioxy group or a lower alkyl group which may be substituted by a halogen atom, a hydroxyl group, a lower alkoxy group, an amino group or a mono- or di-lower alkylamino group;   l: 0 or 1;   m: 0 or an integer of 1 to 3, and   n: an integer of 1 or 2,   a salt thereof, an N-oxide thereof, or a quaternary ammonium salt thereof.   
     
     
       2. The quinuclidine derivative, a salt thereof, or a quaternary ammonium salt thereof according to claim 1, wherein R represents a halogen atom, a lower alkyl group, a hydroxyl group, a lower alkoxy group, a nitro group, a cyano group, an amino group or a mono- or di-lower alkylamino group, and the ring A represents an aryl group having 6 to 14 carbon atoms, a cycloalkyl group having 3 to 8 carbon atoms or a cycloalkenyl group having 3 to 8 carbon atoms, in which said ring may be substituted by a halogen atom, a lower alkyl group, a hydroxyl group, a lower alkoxyl group, a nitro group, a cyano group, an amino group or a mono- or di-lower alkylamino group. 
     
     
       3. The quinuclidine derivative, a salt thereof, or a quaternary ammonium salt thereof according to claim 2, wherein m is 0, and the ring A represents an aryl group, a cycloalkyl group or a cycloalkenyl group which may be substituted by a halogen atom, a lower alkyl group, a hydroxyl group or a lower alkoxy group. 
     
     
       4. The quinuclidine derivative, a salt thereof, or a quaternary ammonium salt thereof according to claim 3, wherein the ring A represents a phenyl group which may be substituted by a halogen atom or a lower alkyl group, or cycloalkyl group. 
     
     
       5. The quinuclidine derivative, a salt thereof, or a quaternary ammonium salt thereof according to any one of claims 2 to 4, wherein X represents a single bond. 
     
     
       6. A quinuclidine derivative, a salt thereof, or a quaternary ammonium salt thereof according to any one of claim 1, which is selected from the group consisting of 3-quinuclidinyl 1-phenyl-1,2,3,4-tetrahydro-2-isoquinolinecarboxylate, 3-quinuclidinyl 1-(4-chlorophenyl)-1,2,3,4-tetrahydro-2-isoquinolinecarboxylate, 3-quinuclidinyl 1-(4-fluorophenyl)-1,2,3,4-tetrahydro-2-isoquinolinecarboxylate, 3-quinuclidinyl 1,2,3,4-tetrahydro-1-(4-tolyl)-2-isoquinolinecarboxylate, and 3-quinuclidinyl 1-cyclohexyl-1,2,3,4-tetrahydro-2-isoquinolinecarboxylate. 
     
     
       7. A pharmaceutical composition which comprises a quinuclidine derivative represented by the following formula (I): ##STR345## where the symbols in the formula have the following meanings: Ring A: (1) an aryl group having 6 to 14 carbon atoms   (3) a cycloalkyl group having 3 to 8 carbon atoms   (4) a cycloakenyl group having 3 to 8 carbon atoms; wherein groups (1) to (5) above may be unsubstituted or substituted by one or more substituents selected from the group consisting of a halogen atom, a hydroxyl group, a lower alkoxy group, a carboxul group, a lower alkoxycarbonyl group, a lower acyl group, a mercapto group, a lower alkylthio group, a sulfonyl group, a lower alkylsulfonyl group, a sulfinyl group, a lower alkylsulfinyl group, a sulfonamido group, a lower alkanesulfonamido group, a carbamoyl group, a thiocarbamoyl group, a mono- or di-lower aklylcarbamoyl group, a nitro group, a cyano group, an amino group, a mono- or di-lower alkylamino group, a methylenedioxy group, an ethylenedioxy group and a lower alkyl group which may be substituted by a halogen atom, a hydroxyl group, a lower alkoxyl group, an amino group or mono- or di-lower alkylamino group     X: a single bond or a methylene group;   R: a halogen atom, a hydroxyl group, a lower alkoxy group, a carboxyl group, a lower alkoxycarbonyl group, a lower acyl group, a mercapto group, a lower alkylthio group, a sulfonyl group, a lower akylsulfonyl group, a sulfinyl group, a lower alkylsufinyl group, a sulfonamido group, a lower alkanesulfonamido group, a carbamoyl group, a thiocarbamoyl group, a mono- or di-lower alkylcarbamoyl group, a nitro group, a cyano group, an amino group, a mono- or di-lower alkylamino group, a methylenedioxy group, an ethylenedioxy group or a lower alkyl group which may be substituted by a halogen atom, a hydroxyl group, a lower alkoxy group, an amino group or a mono- or di-lower alkylamino group;   l: 0 or 1;   m: 0 or an integer of 1 to 3, and   n: an integer of 1 or 2, or   a salt thereof, an N-oxide thereof, or a quaternary ammonium salt thereof,   and a pharmaceutically acceptable carrier.